De-escalation of anti-platelet therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a narrative review

Objective:Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI).In current clinical situation, availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) has enabled physicians to switch among therapies owing to specific clinical scenarios.Although optimum time, loading dose and interval of transition between P2Y12 inhibitors is still controversial and needs further evidence, switching between oral inhibitors frequently occurs in clinical practice for several reasons.Data sources:This review was based on data in articles published in PubMed up to June 2018, with the following keywords "antiplatelet therapy" , "ACS" , "PCI" , "ticagrelor" and "clopidogrel" .Study selection:Original articles and critical reviews on de-escalation strategy in ACS patients after PCI were selected.References of the retrieved articles were also screened to search for potentially relevant papers.Results:Safety concerns associated with switching between antiplatelet agents, has prompted the use of clopidogrel for patients with ACS especially after PCI as a de-escalation strategy.Practical considerations for de-escalating therapies in patients with ACS such as reducing dose of P2Y12 inhibitors or shortening duration of DAPT (followed by aspirin or P2Y12 receptor inhibitor monotherapy) as potential options are yet to be standardized and validated.Conclusions:Current review will provide an overview of the pharmacology of common P2Y12 inhibitors, definitions of deescalation and different de-escalating strategies and its outcomes, along with possible direction to be explored in de-escalation.

Antibiotics De-Escalation in the Treatment of Ventilator-Associated Pneumonia in Trauma Patients： A Retrospective Study on Propensity Score Matching Method

Background： Antimicrobial de-escalation refers to starting the antimicrobial treatment with broad-spectrum antibiotics, followed by narrowing the drug spectrum according to culture results. The present study evaluated the effect of de-escalation on ventilator-associated pneumonia （VAP） in trauma patients. Methods： This retrospective study was conducted on trauma patients with VAP, who received de-escalation therapy （de-escalation group） or non-de-escalation therapy （non-de-escalation group）. Propensity score matching method was used to balance the baseline characteristics between both groups. The 28-day mortality, length of hospitalization and Intensive Care Unit stay, and expense of antibiotics and hospitalization between both groups were compared. Multivariable analysis explored the factors that influenced the 28-day mortality and implementation of de-escalation. Results： Among the 156 patients, 62 patients received de-escalation therapy and 94 patients received non-de-escalation therapy. No significant difference was observed in 28-day mortality between both groups （28.6% vs. 23.8%, P = 0.620）. The duration of antibiotics treatment in the de-escalation group was shorter than that in the non-de-escalation group （11 [8-13] vs. 14 [8-19] days, P = 0.045）. The expenses of antibiotics and hospitalization in de-escalation group were significantly lower than that in the non-de-escalation group （6430 ± 2730 vs. 7618 ± 2568 RMB Yuan, P = 0.043 and 19,173 ± 16,861 vs. 24,184 ± 12,039 RMB Yuan, P = 0.024, respectively）. Multivariate analysis showed that high Acute Physiology and Chronic Health Evaluation Ⅱ （APACHE Ⅱ） score, high injury severity score, multi-drug resistant （MDR） infection, and inappropriate initial antibiotics were associated with patients＇ 28-day mortality, while high APACHEⅡ score, MDR infection and inappropriate initial antibiotics were independent factors that prevented the implementation of de-escalation. Conclusions： De-escalation strategy in the treatment of trauma patients with VAP could reduce the duration of antibiotics treatments and expense of hospitalization, without increasing the 28-day mortality and MDR infection.

Discontinuation of therapy in inflammatory bowel disease: Current views

The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease(IBD).The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission.In patients with achieved long-term remission,the question of de-escalation or discontinuation of therapy arises,considering the possible side effects and economic burden of long-term therapy.For each of the drugs used in IBD(5-aminosalycaltes,immunomodulators,biological drugs,small molecules)there is a risk of relapse.Furthermore,studies show that more than 50%of patients who discontinue therapy will relapse.Based on the findings of large studies and meta-analysis,relapse of disease can be expected in about half of the patients after therapy withdrawal,in case of monotherapy with aminosalicylates,immunomodulators or biological therapy.However,longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor.It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking.Before making a decision on discontinuation of therapy,it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse.Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse.Several other predictive factors have also been identified,such as:High Crohn's disease activity index or Harvey Bradshaw index,younger age(<40 years),longer disease duration(>40 years),smoking,young age of disease onset,steroid use 6-12 months before cessation.An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs.The decision to discontinue therapy must be based on individual approach,taking into account the severity,extension,and duration of the disease,the possibility of side adverse effects,the risk of relapse,and patient’s preferences.

Mucosal healing in inflammatory bowel disease： Maintain orde-escalate therapy

In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.

The Utility of Procalcitonin as a Biomarker to Limit the Duration of Antibiotic Therapy in Adult Sepsis Patients

Introduction: With rising global antibiotic resistance, stewardship programs aimed at controlling multi-drug resistant (MDR) pathogens have begun to gain acceptance. These programs stress appropriate antibiotic selection, dosage and duration. A growing literature suggests serum procalcitonin (PCT) levels may be useful in guiding antibiotic duration and de-escalation. This report sought to evaluate the evidence-based data available from prospective randomized controlled trials (RCT) on the role of PCT in guiding reductions in antibiotic duration in adult sepsis patients. Methods: A comprehensive search of all published prospective RCT(s) on the use of PCT as a tool for guiding antibiotic therapy in adult sepsis patients was conducted using PubMed, Medline Plus and Google Scholar (2007-2013). Keywords searched included, “procalcitonin”, “sepsis-therapy”, “sepsis biomarker”, “antibiotic duration”, “drug de-escalation”, and “antimicrobial stewardship”. Results:?Four RCT(s) involving 826 adult sepsis patients have evaluated the role of serum PCT levels to guide criteria for cessation of antibiotic therapy based either on specific PCT levels or PCT kinetics. Bouadma?et al.?(N = 621) stopped antibiotics when the PCT concentration was <80% of the peak PCT value, or the absolute PCT concentration was <0.5 μg/L. The PCT arm showed a 2.7-day reduction in antibiotics. Schroeder?et al.?(N = 27) discontinued antibiotics if clinical signs of infection improved and the PCT value decreased to <1 ng/mL or to <35% of the initial value within three days. The PCT arm had a 1.7-day reduction in antibiotics. Hochreiter?et al.?(N = 110) ceased antibiotics when the PCT decreased to <1 ng/mL, or to 25% - 35% of the initial value over three days if the value was >1 ng/mL. The PCT arm showed a 2-day reduction in antibiotics. Finally, Nobre?et al.?(N = 68) stopped antibiotics when PCT levels decreased by 90% or more from the initial value, but not prior to Day 3 (if baseline PCT measured <1 μg/L) or Day 5 (if baseline PCT measured ≥1 μg/L). The PCT arm showed a 4-day reduction in antibiotics. Overall, reduction of PCT levels to 10% - 35% of the initial concentration, to <80% of the peak PCT value, or to an absolute PCT value of <1 μg/L warranted antibiotic discontinuation 1.7 to 4 days earlier. No study reported a significant difference in mortality between the PCT arm and the control arm (p< 0.05). Conclusions: PCT-guided early cessation of antibiotic therapy in adult sepsis patients is associated with a significant decrease in antibiotic days, with no effect on overall mortality. Measurement of serum PCT levels may have a role in antimicrobial stewardship programs aimed at limiting antibiotic therapy duration, decreasing the selective pressure on drug-resistant bacterial strains and reducing hospital costs.

Efficacy and safety of different dual antiplatelet strategies in patients undergoing percutaneous coronary intervention:A systematic review and network meta-analysis

Background:Dual antiplatelet therapy(DAPT)is key for preventing ischaemic events post-percutaneous coronary intervention(PCI).Various DAPT modifications like the shortened duration or P2Y12 inhibitor(P2Y12i)de-escalation are implemented to reduce bleeding risk.However,these strategies lack direct comparative studies.This study aimed to assess the efficacy and safety of such DAPT strategies,including de-escalated and short DAPT,in patients undergoing PCI.Methods:We searched PubMed,Embase,Cochrane Central Register of Controlled Trials,and ClinicalTrials.gov databases for relevant randomized controlled trials(RCTs).We performed a network meta-analysis(NMA)to estimate risk ratios(RRs)and 95%confidence intervals(CIs).The primary efficacy endpoint was major adverse cardiac events(MACEs),and the primary safety endpoint was major bleeding.Secondary endpoints included individual components of MACEs and net adverse clinical events(NACEs).Results:A total of 17 RCTs comprising 53,156 patients(median age,62.0 years,24.8%female)were included.NMA suggested that de-escalation DAPT was associated with a significantly lower risk of MACEs(risk ratio[RR]=0.79,95%confidence interval[CI]=0.64-0.98),bleeding(RR=0.63,95%CI=0.49-0.82),and NACEs(RR=0.69,95%CI=0.60-0.79)compared with standard DAPT.Short DAPT followed by P2Y12i monotherapy exhibited a significantly decreased risk of major bleeding(RR=0.63,95%CI=0.46-0.86)compared with standard DAPT.Conclusions:De-escalation DAPT was the most effective strategy for preventing the risk of MACEs without increasing bleeding events,while short DAPT followed by P2Y12i monotherapy was the most effective strategy for reducing the risk of bleeding among patients undergoing PCI.

Current Status of Human Papillomavirus-Related Head and Neck Cancer: From Viral Genome to Patient Care

Human papillomavirus(HPV)infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers.Up to 38%–80%of head and neck squamous cell carcinoma(HNSCC)in oropharyngeal location(OPSCC)and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7.Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors,clinical trials on de-escalation treatment strategies for these patients have been studied.It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible.Moreover,understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy.This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions.With the advent of various sequencing technologies,further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.